Anthracycline antibiotics are a widely investigated class of compounds having antitumor activity. Particularly, doxorubicin (DXR) has been used for a long time in antitumor chemotherapy protocols.
The clinical usefulness of anthracycline antibiotics is limited by serious side effects such as cardiomyopathy, bone-marrow depression, gastrointestinal tract mucositis and, if there is drug leakage at the injection site, local tissue necrosis.
Particularly, local side effects are represented by sloughing ulcerations and occur when the drug is inadvertently extravasated during administration or oozes out through compromised vein walls. Damage from extravasation is not immediately apparent, but comes out days later and slowly progresses to involve superficial and deep structures, such as soft tissues and nerves and tendons as well. The severe course of this type of lesions, which can be experimentally reproduced in animal models (see Balsari A., et al, Chemotherapy 5: 324-329, 1989), is due to the long term persistence of residual active drug at the extravasation sites.
Another peculiar side effect consists in alopecia, which is due to the inhibiting activity exerted by anthracyclines on the continuously growing cells of hair roots. Alopecia occurs in almost the totality of the patients treated with anthracycline drug. Such effect is not life endangering per se, but severely harasses the patient and deteriorates the quality of life.
Many attempts have been made to reduce the toxicity of anthracycline antibiotics, while retaining substantially unaffected the antitumor activity thereof. For this purpose, two main approaches have been taken: (a) synthesis of DXR analogues and derivatives; and (b) combination with substances which are thought likely to interfere with factors claimed to be responsible for the toxic effects of these drugs, such as vitamin E, ubiquinone, chelating agents and the like.
However, no efficient method of treatment has been so far described for the above-mentioned highly distressing tissue lesions. In a number of cases surgical intervention is considered for wide removal of the lesions in the attempt of salvaging structures and retain function. In some cases, limb amputation and/or skin grafting may be necessary. Local infiltration at extravasation sites with sodium bicarbonate or hyaluronidase or saline solution is of limited usefulness, if any.
Many approaches have been suggested to reduce alopecia incidence and extent by decreasing the scalp blood flow with the use of tourniquets, tight refrigerated caps, etc.
So far, the above-described problems have not satisfactorily been solved.